Description: (Applicant's Abstract) Management of chronic painful syndromes presents a tremendous challenge to the medical field as current pain management approaches with narcotics, such as morphine, carry adverse side effects such as sedation, constipation, tolerance and addiction. Therefore, a greater understanding of pathophysiological mechanisms that lead to a chronic pain state is needed for development of novel and effective therapies with minimal side effects. Recently, we demonstrated that when a conjugate of substance P (SP) and the ribosome-inactivating protein saporin (SAP) is infused into the spinal cord, the SP-SAP conjugate is specifically internalized and cytotoxic to lamina I spinal cord neurons that express the substance P receptor (SPR). This treatment leaves responses to mild noxious stimuli unchanged, but profoundly attenuates responses to highly noxious stimuli and to mechanical and thermal hyperalgesia. Using the intrathecal infusion of SP-SAP in the rat spinal cord as our model we propose: to investigate whether this treatment can alleviate inflammatory and/or neuropathic persistent pain states (Aim 1); to further define the rostral brain areas these neurons project to and the other receptors and neurotransmitters that are expressed by lamina I SPR-expressing neurons (Aim 2); to determine the functional role of neurons that express the SPR in nociceptive processing and hyperalgesia, and whether these SPR expressing neurons are functionally different from nociceptive neurons that do not express the SPR (Aim 3); and to determine whether reorganization of the spinal cord and dorsal root ganglia occurs following SP-SAP treatment and whether morphine is still effective in attenuating nociceptive responses (Aim 4). Information from these investigations will provide significant insight into the neurochemistry of spinal nociceptive signaling and whether SP-SAP treatment shows promise for developing non-opioid therapies to control chronic pain in humans.